WO2019074241A1 - Inhibitor against interaction between pd-1 and pd-l1, comprising phenylacetylene derivative - Google Patents

Abstract

The present invention relates to a compound represented by Chemical Formula 1 in the description or a pharmaceutically acceptable salt thereof. A compound and a pharmaceutically acceptable salt thereof according to the present invention suppress interaction between the programmed death 1 (PD-1) protein and the programmed death-ligand 1 (PD-L1) protein, thereby finding useful applications in the prevention or treatment of diseases associated therewith.

Description

Interaction inhibitor of PD-1 and PD-L1 containing a phenylacetylene derivative

The present invention relates to novel small molecule compounds which can be effectively used for the prevention or treatment of diseases related thereto by inhibiting the interaction between the protein of Programmed death 1 (PD-1) and the protein of Programmed death-ligand 1 (PD-L1) To a pharmaceutical composition.

Programmed death 1 (PD-1) protein plays an important role in down-regulating the immune system as a surface receptor for immune cells such as activated T cells, B cells, and bone marrow cells. Programmed death-ligand 1 (PD-L1) protein is a transmembrane protein that binds to the PD-1 receptor and regulates its activation and inhibition.

PD-L1 of cancer cells binds to PD-1 of immune cells and downregulates immune cells, thereby making it possible to avoid the immune system. Therefore, PD-1 and PD-L1 antibody drugs that inhibit the binding of PD-1 and PD-L1 are being developed as immuno-oncology therapies, and some of them have been approved and used. However, antibody drugs are expensive due to their high molecular weight compared to small molecule compounds, high production costs due to difficult manufacturing processes, and are highly likely to have immune side effects such as acute immune hypersensitivity, serum diseases, and antibody production. In addition, until now, it has been developed as an intravenous drug, and adverse side effects such as chills / dyspnea / itching / facial appearance / dizziness / fever /

Accordingly, the inventors of the present invention have been studying a novel small molecule compound capable of replacing an antibody drug, and thus the present inventors have found that the phenylacetylene derivative described in the present invention effectively inhibits the binding action of PD-1 and PD-L1 to prevent cancer, And thus the present invention has been completed.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

X ₁ = X ₂ can be N = CR ₁₁ , R ₁₁ -C = N, N = N, C = C;

R ₁ is _{(CH) n -CO 2 H,} OR 9, CO- (NH-R 9), CO-R 9, NH-R 9, N (R 9) 2, N (R 9) (R 10) ,

, Where n may be from 0 to 4;

R ₂ is selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, CN, CO- (C _1-4 alkyl), OH, O- (C _1-4 alkyl), O- (CH ₂ ) _m- (CH _{2) m} - alkyl cycle, O- (CH _{2) m} - heterocyclyl, NH _2, NH- (C _1-4 alkyl), N (C _{1-4 alkyl) 2, NH- (CH 2)} m -Heteroaryl, SO ₂ - (C _1-4 alkyl), where m can be from 0 to 4;

(C _1-4 alkyl), NH ₂ , NH- (C _1-4 alkyl), and R ₃ , R ₆ , R ₇ , R ₈ and R ₁₁ are independently selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, ), N (C _1-4 alkyl) ₂ , SO ₂ - (C _1-4 alkyl), CO-NH ₂ , CO- (NH-R ₉ );

R ₄ is hydrogen, halogen, C _1-4 alkyl, CN, CO- (C _1-4 alkyl), OH, O- (C _1-4 alkyl), NH _2, NH- (C _1-4 alkyl), N (C _1-4 alkyl) ₂ ;

R ₅ is aryl, heteroaryl, alkyl-cycle, may be a heterocycle, which is hydrogen, halogen, C _1-4 alkyl, CN, OH, O- (C _{1-4 alkyl), O- (CH 2) q} - O, NH ₂ , NH- (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , SO ₂ - (C _1-4 alkyl), wherein q is 1 to 4 Lt; / RTI >

R ₉ and R ₁₀ may be C _1-4 alkyl which may be substituted by halogen, C _1-3 alkyl, CN, OH, CO ₂ H, CONH ₂ , NH ₂ , NH- (C _1-3 alkyl) C _1-3 alkyl) ₂ ,

, N-CO-C _1-4 alkyl, wherein x can be from 0 to 4;

Halogen can be F, Cl, Br.

Preferably, R ₁ is OR ₉ , NH-R ₉ ,

Lt; / RTI >

Preferably, R ₂ is hydrogen, halogen, methyl, ethyl, CN, OH, OMe, OEt, O- (CH ₂₎ - heteroaryl, O- (CH _{2) 2} - heteroaryl, O- (CH ₂₎ -alkyl cycle, O- (CH _{2) 2} - cycle alkyl, O- (CH ₂₎ - heterocycle, O- (CH _{2) 2} - _{heterocyclic, NH 2, NHMe, NMe2,} N- (CH 2) - Heteroaryl, N- (CH ₂ ) ₂ -heteroaryl.

_{Preferably, R 3, R 4, R} 6, R 7, R 8, R 11 is hydrogen, halogen, methyl, ethyl, cyclopropyl, CN, OH, OMe, OEt, NH _2, NHMe, NMe ₂ il have.

Preferably R ₅ is phenyl, thiophene, pyridine, pyrimidine, pyridazine, oxazole,

,

,

One can have, which hydrogen, halogen, methyl, ethyl, CN, OH, OMe, OEt , O- (CH 2) -O, O- (CH 2) 2 -O, NH 2, NHMe, NMe 2, SO 2 Me < / RTI >

Preferably, R ₉ and R ₁₀ may be C _1-4 alkyl, which may be halogen, methyl, ethyl, CN, OH, CO ₂ H, CONH ₂ , NH ₂ , NHMe, NHEt, NMe ₂ , -Me, < / RTI >

Representative examples of the compound represented by the above formula (1) are as follows:

1) ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

2) 1 - ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine- 2-

3) Ethyl) pyridazin-3-yl) methyl) amino) ethan-1-ol

4) ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3- yl) ethynyl) pyridazin-

5) Preparation of 1 - ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Carboxylic acid

Ethynyl) pyridazin-3-yl) methyl) amino) ethane-2-carboxylic acid 1-

7) ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

8) Synthesis of 1 - ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine-

9) Preparation of 2 - (((6 - ((2-cyano- [

Ethynyl) pyridazin-3-yl) methyl) glycine (2-methyl-

Ethyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid (2-methyl-

Ethynyl) pyridazin-3-yl) methyl) amino) ethane-1, 2- - All

13) ((5-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

Ethyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid (2-methyl-

Ethynyl) pyridazin-3-yl) methyl) amino) ethane-1, 2'- - All

16) ((6- ((2-methyl-3- (pyridin-4- yl) phenyl) ethynyl) pyridazin-

17) ((6 - ((2-methyl-2 ', 3', 4 ', 5'-tetrahydro- [1,1'- biphenyl] -3- yl) ethynyl) pyridazin- ) Methyl) glycine

Ethynyl) pyridazin-3-yl) methyl) glycine (2-methyl-3-

19) ((6- ((2-hydroxy- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

20) ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-

21) ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-

22) (4- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

23) 2 - ((4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) amino)

24) (2- ((5-cyanopyridin-3-yl) methoxy) -4 - ((2-

Ethynyl) -2 - (((2 (R) -2,5-dihydrobenzo [ -Hydroethyl) amino) methyl) phenoxy) methyl) nicotinonitrile

26) (2 - ((5-cyanopyridin-3-yl) methoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- -2-methylphenyl) ethynyl) benzyl) -L-serine

Ethynyl) pyridazin-3-yl) methyl) glycine (2-methyl- [1,1'-biphenyl]

Yl) ethynyl) pyridazin-3-yl) methyl) - < / RTI & Amino) ethan-1-ol

29) ((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Pyridazin-3-yl) methyl) glycine

30) 2 - (((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Ethynyl) pyridazin-3-yl) methyl) amino) ethan-1-ol

Ethynyl) pyridin-2-yl) methyl) amino (2-methylphenyl) ) Ethan-1-ol

32) (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

Ethyl) benzyl) amino) ethan-1-ol (Compound No. 2) was obtained in the same manner as in Example 1,

34) (2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) benzyl ) Glycine

35) To a solution of 2 - ((2- (cyclohexylmethoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- Yl) benzyl) amino) ethan-1-ol

Ethynyl) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl) glycine

Ethynyl) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl (2-methyl- ) Amino) ethan-1-ol

Ethynyl) -2- (2- (piperidin- 1 -yl) ethoxy) benzyl) glycine (2-methyl-

Ethynyl) -2- (2- (piperidin-1-yl) ethoxy) benzyl) -2,3- Amino) ethane-1-ol

Ethynyl) -2- (2- (4-methylpiperazin-1-yl) ethoxy) benzyl) Glycine

Ethoxy) -2- (2- (4-methylpiperazin-1-yl) ethoxy) ) ≪ / RTI > benzyl) amino) ethan-

Ethynyl) -2- (2-morpholinoethoxy) benzyl) glycine (2-methyl-

Ethynyl) -2- (2-morpholinoethoxy) benzyl) amino) ethane-l- All

44) 1- (4 - ((2-Methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl) piperidine- mountain

45) Preparation of 3 - ((3- (cyclohexylmethoxy) -4 - ((2-hydroxyethyl) amino) methyl) phenyl) ethynyl- [1,1'-biphenyl] -2-carbonitrile .

In addition, the present invention provides a process for producing a compound represented by the formula (1), which is represented by the following reaction scheme 1 and scheme 2:

[Reaction Scheme 1]

The definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , X ₁ and X ₂ are as defined above. The specific reaction of Reaction Scheme 1 is as follows.

The step 1 is a step of reacting the compound represented by the formula 2 and the compound represented by the formula 3 to prepare the compound represented by the formula 4. It is preferable to react under _{CuI, Pd (PPh 3) 4} , NEt 3 exists, the solvent is preferably THF.

The step 2 is a step of reacting the compound represented by the formula 4 and the compound represented by the formula 5 to prepare the compound represented by the formula 6. It is preferable to react under _{CuI, Pd (PPh 3) 4} , NEt 3 exists, the solvent is preferably THF.

The step 3 is a step of reducing the compound represented by the formula 6 to prepare the compound represented by the formula 7. It is preferable to carry out the reaction in the presence of Dibal-H [( i- Bu) ₂ AlH], and the solvent is preferably CH ₂ Cl ₂ .

Step 4 is a step of reacting the compound represented by Formula 7 with the compound represented by Formula 8 to prepare the compound represented by Formula 1. NaH (OAc) ₃ , and the solvent is preferably CH ₂ Cl ₂ .

[Reaction Scheme 2]

Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , X ₁ and X ₂ are as defined above and OR is the same as R ₂ . The specific reaction of Reaction Scheme 2 is as follows.

The step 1 is a step of reacting the compound represented by the formula (9) and the compound represented by the formula (10) to prepare the compound represented by the formula (11). PPh ₃ , diisopropyl azodicarboxylate, and the solvent is preferably THF.

The step 2 is a step of reacting the compound represented by the formula (12) and the compound represented by the formula (3) to prepare the compound represented by the formula (13). CuI, PdCl ₂ (PPh ₃ ) ₂ , NEt ₃ , and the solvent is preferably THF.

Step 3 is a step of reacting the compound represented by Formula 13 and the compound represented by Formula 14 to prepare the compound represented by Formula 15. Pd (PPh _{3) 4,} it is preferred to react under the presence CsCO _3, and the solvent is preferably water and dioxane.

Step 4 is a step of reacting the compound represented by Formula 15 and the compound represented by Formula 11 to prepare the compound represented by Formula 16. CuI, PdCl ₂ (PPh ₃ ) ₂ , NEt ₃ , and the solvent is preferably THF.

Step 5 is a step of reducing the compound of Formula 16 to prepare the compound of Formula 17. It is preferable to carry out the reaction in the presence of Dibal-H [( i- Bu) ₂ AlH], and the solvent is preferably CH ₂ Cl ₂ .

Step 6 is a step of reacting the compound represented by Formula 17 and the compound represented by Formula 8 to prepare the compound represented by Formula 18. NaH (OAc) ₃ , and the solvent is preferably CH ₂ Cl ₂ .

The compounds according to the present invention and their pharmaceutically acceptable salts are useful for the prevention or treatment of diseases related to this by inhibiting the interaction of the Programmed death 1 (PD-1) protein with the Programmed death-ligand 1 (PD-L1) Lt; / RTI >

Preferred embodiments are provided to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Various methods for synthesizing the starting materials for synthesizing the compounds of the present invention are known. When the starting materials are commercially available, they can be purchased from a supplier. The reagent supply sources include, but are not limited to, Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Combi-blocks, and Dae-Jung. In addition, all commercially available materials were used without further purification, except as otherwise provided.

Example 1 Preparation of ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl)

Step 1) Preparation of methyl 6-ethynylpyridazine-3-carboxylate

Methyl-6-chloropyridazin-3-carboxylate 10.01 g, Cri methyl when ethynyl is 8.55 g, CuI 1.10 g, Pd (PPh 3) 4 6.72 g, Et 3 N 8.81 g, THF 100 mL of the mixture was 70 ° C < / RTI > for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of methanol, 10 g of K ₂ CO ₃ was added dropwise, and the mixture was stirred at room temperature for 3 hours. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6.21 g of methyl 6-ethynylpyridazine-3-carboxylate.

[M + H] < ⁺ >: 163

Step 2) Preparation of methyl 6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-

Pyridazin-3-carboxylate 1.71 g, 3- bromo-2-methyl-biphenyl-ethynyl-methyl-6- 2.20 g, CuI 0.13 g, Pd (PPh 3) 4 0.81 g, Et 3 N 1.07 g, THF 20 mL Was stirred at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.73 g of methyl 6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carboxylate.

[M + H] < ⁺ >: 329

Step 3) Preparation of (6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-

Methyl 6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) a Dibal-dihydro-pyridazin-3-carboxylate 1.65 g, a mixture of CH ₂ Cl ₂ at 0 ° C 3 mL -H (( i- Bu) ₂ AlH, 1 M in toluene) and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was treated with sodium potassium tartrate solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.23 g of (6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde.

[M + H] < ⁺ >: 298

Step 4) Preparation of methyl ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) glycinate

Ethylidene) pyridazine-3-carbaldehyde, 0.14 g of methyl glycinate hydrochloride, 0.11 g of Et ₃ N, and 0.17 g of 2- ((2-methyl- [ 0.22 g of NaBH (OAc) _{3 and} 3 mL of CH ₂ Cl ₂ was stirred at room temperature for 3 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3yl) methyl) glycinate 0.10 g was obtained.

[M + H] < ⁺ >: 372

Step 5) Production of ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

Ethyl) pyridazin-3-yl) methyl) glycinate, 0.07 g of LiOH, 3 mL of MeOH Was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and aqueous NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.06 g of ((6- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 358

Example 2 Preparation of 1 - ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine-

Example 1 To a solution of (6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde and methyl piperidine- Yl) ethynyl] pyridazine-3-carboxamide was obtained in the same manner as in Example 1, Steps 4 and 5, except that 1 - ((6- ( Yl) methyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 412

Example 3) Synthesis of 2 - ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) amino) Manufacturing

Using the (6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde and ethanolamine prepared in Step 1 of Example 1, Ethynyl) pyridazin-3-yl) methyl) amino) ethane-1-carboxylate was obtained in the same manner as in Step 1 of Example 1, 1-ol.

[M + H] < ⁺ >: 344

Example 4 Preparation of ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

Step 1) Preparation of 3-bromo-5-fluoro-2-methyl- [1,1'-biphenyl]

1-bromo-5-fluoro-3-iodo-2-methyl-benzene 5.00 g, phenyl view it in acid _{1.75 g, Pd (PPh 3)} 4 0.83 g, Na 2 CO 3 1.52 g, water 2 mL, ethanol 2 mL, and toluene 20 mL was stirred at 120 ° C for 6 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.11 g of 3-bromo-5-fluoro-2-methyl- [1,1'-biphenyl].

[M + H] < ⁺ >: 266

Step 2) Production of ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

((6 - ((5-fluoro-4-fluoro-phenyl) Methyl] - [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 376

Example 5) Synthesis of 1 - ((6 - ((5-fluoro-2-methyl- [1,1'- biphenyl] -3-yl) ethynyl) pyridazin- Preparation of 2-carboxylic acid

(5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde obtained in the process of Example 4 Methylpiperidine-2-carboxylate hydrochloride, 1 - ((6 - ((5-fluoro-2-methyl- [ Yl) ethynyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 430

Example 6) Synthesis of 2 - ((6 - ((5-fluoro-2-methyl- [1,1'- biphenyl] -3- yl) ethynyl) pyridazin- Ethan-1-ol

(5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde obtained in the process of Example 4 and ethanolamine ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine- 3 as a white solid. Yl) methyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 362

Example 7 Preparation of ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

((6 - ((2-cyano- [1,1'-biphenyl] -3- (2-chloro- Yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 369

Example 8) Preparation of 1 - ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine-

((6-formylpyridazin-3-yl) ethynyl) - [1,1'-biphenyl] -2-carbonitrile obtained in the preparation of Example 7 and Carboxylate hydrochloride, 1 - ((6 - ((2-cyano- [1,1'-biphenyl] -3- Ethynyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 423

Ethynyl) pyridazin-3-yl) methyl) amino) ethane-l- (2-cyano- [1,1'- Manufacturing

((6-formylpyridazin-3-yl) ethynyl) - [1,1'-biphenyl] -2-carbonitrile obtained in the preparation of Example 7 and (2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-ylmethyl ester was prepared in the same manner as in step 1 of Example 1, Yl) methyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 355

Example 10 Preparation of ((4-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

Step 1) Preparation of methyl 4,6-dichloropyridazine-3-carboxylate

10.0 g of methyl 4-chloro-6-hydroxypyrazine-3-carboxylate and 20.5 g of POCl _{3 was} stirred at 70 ° C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and ice water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.13 g of methyl 4,6-dichloropyridazine-3-carboxylate.

[M + H] < ⁺ >: 206

Step 2) Preparation of ((4-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

((4-chloro-6 - ((2-methyl- [1,1,1-dioxaborolan- -Biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 392

Example 11) 1 - ((4-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidin- - Preparation of carboxylic acid

(4-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde obtained in the preparation of Example 10 and methylpiperidine (2-methyl- [l, r-biphenyl] -3-yl) -2-oxo-pyrrolidine hydrochloride in the same manner as in Example 1, Steps 4 and 5, Ethynyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 446

Example 12) 2 - (((4-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- -1-ol

Ethynyl) pyridazine-3-carbaldehyde and ethanolamine obtained in the preparation of Example 10 (4-chloro-6- ( ((4-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Yl) methyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 378

Example 13 Preparation of ((5-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl)

Step 1) Preparation of ethyl 5,6-dichloropyridazine-3-carboxylate

10.0 g of ethyl 5-chloro-6-hydroxypyrazine-3-carboxylate and 20.5 g of POCl _{3 was} stirred at 70 ° C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and ice water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.85 g of ethyl 5,6-dichloropyridazine-3-carboxylate.

[M + H] < ⁺ >: 206

Step 2) Preparation of ((5-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

((5-chloro-6 - ((2-methyl- [1,1,1] -thiophene-3- carboxylic acid ethyl ester in the same manner as in Example 1, Steps 1, 2, -Biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 392

Example 14) 1 - ((5-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3- yl) ethynyl) pyridazin-3- yl) methyl) piperidin- - Preparation of carboxylic acid

(5-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde obtained in the preparation of Example 13 and methyl piperidine -2-carboxylate hydrochloride, 1 - ((5-chloro-6 - ((2-methyl- [ Ethynyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 446

Example 15) Synthesis of 2 - (((5-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- -1-ol

( 5-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carbaldehyde obtained in the preparation of Example 13 and ethanolamine ((5-chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Yl) methyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 378

Example 16 Preparation of ((6 - ((2-methyl-3- (pyridin-4-yl) phenyl) ethynyl) pyridazin-3-yl) methyl)

((6 - ((2-methyl-3- (pyridin-4-yl) phenyl) -phenylamine was obtained by the same method as in Example 1, Steps 2, 3, ) Ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 359

Example 17 Synthesis of ((6 - ((2-methyl-2 ', 3', 4 ', 5'-tetrahydro- [1,1'- biphenyl] -3-yl) ethynyl) pyridazine- Yl) methyl) glycine < / RTI >

Step 1) Preparation of 3'-chloro-2'-methyl-2,3,4,5-tetrahydro-1,1'-biphenyl

(3-chloro-2-methylphenyl) boronic acid in 4.01 g, 1- bromo-1-cyclopropyl-hexyne 5.89 g, CuI 1.39 g, cyclohexane diamine, _{0.83 g, CsCO 3 13.08 g,} dioxane 30 mL mixture of 80 ° C Followed by stirring for 24 hours. After completion of the reaction, the solvent was removed under reduced pressure, and ethyl acetate and water were added thereto to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.23 g of 3'-chloro-2'-methyl-2,3,4,5-tetrahydro-1,1'-biphenyl.

[M + H] < ⁺ >: 207

(2-methyl-2 ', 3', 4 ', 5'-tetrahydro- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Yl) methyl) glycine

((6- (3-chloro-2'-methyl-2,3,4,5-tetrahydro-1,1'-biphenyl) ((2-methyl-2 ', 3', 4 ', 5'-tetrahydro- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3-yl) methyl) .

[M + H] < ⁺ >: 362

Example 18) ((6 - ((2-Methyl-3- (1 -methyl-1,2,3,6-tetrahydropyridin-4- yl) phenyl) ethynyl) pyridazin- ) Preparation of glycine

((6 - ((2-methyl-3- (2-methyl-3-phenylpropyl) -1H- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 377

Example 19 Preparation of ((6 - ((2-hydroxy- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

((6 - ((2-hydroxy- [1,1 ' -biphenyl] - (3-bromo-2-hydroxyphenyl) Yl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 360

Example 20 Preparation of ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-2yl) methyl)

(5 - ((2-methyl- [l, l ' -biphenylsulfonyl) piperidine was obtained in the same manner as in Example 1, Steps 1, 2, 3, 4 and 5, using 5-bromo picoline aldehyde and methyl glycinate hydrochloride. ] -3-yl) ethynyl) pyridin-2yl) methyl) glycine.

[M + H] < ⁺ >: 357

Example 21 Preparation of ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-3yl) methyl)

(5 - ((2-methyl- [l, l ' -biphenylsulfonyl) -methanone hydrochloride was obtained in the same manner as in Example 1, Steps 1, 2, 3, ] -3-yl) ethynyl) pyridin-3yl) methyl) glycine.

[M + H] < ⁺ >: 357

Example 22 Preparation of (4- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

(4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -ethanone was obtained in the same manner as in Example 1, Steps 2, 3, Benzyl) glycine.

[M + H] < ⁺ >: 356

Example 23 Preparation of 2 - ((4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) amino) ethan-

Ethynylbenzaldehyde was prepared in the same manner as in Example 1, Steps 2, 3 and 4 except that 2 - ((4 - ((2-methyl- [ ) Benzyl) amino) ethan-l-ol.

[M + H] < ⁺ >: 342

Example 24 Synthesis of (2 - ((5-cyanopyridin-3-yl) methoxy) -4 - ((2- Production of glycine

Step 1) Preparation of 5 - ((5-bromo-2-formylphenoxy) methyl) nicotinonitrile

A mixture of 2.00 g of 4-bromo-2-hydroxy-benzaldehyde, 0.26 g of NaH and 20 mL of DMF was stirred at 0 ° C for 1 hour and then treated with 1.51 g of 5- (chloromethyl) -3-pyridinecarbonitrile . After the temperature was raised to room temperature, the mixture was stirred for 4 hours. After completion of the reaction, ethyl acetate was added thereto and the mixture was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.33 g of 5 - ((5-bromo-2-formylphenoxy) methyl) nicotinonitrile.

[M + H] < ⁺ >: 318

Step 2) Preparation of 5 - ((5-ethynyl-2-formylphenoxy) methyl) nicotinonitrile

5 - ((5-bromo-2-formyl-phenoxy) methyl) nicotinoyl nitrile 2.20 g, when Cri methyl ethynyl is 102 g, CuI 0.13 g, Pd (PPh 3) 4 0.80 g, Et 3 N 1.05 g , 22 mL of THF was stirred at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of methanol, 10 g of K ₂ CO ₃ was added dropwise, and the mixture was stirred at room temperature for 3 hours. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.50 g of 5 - ((5-ethynyl-2-formylphenoxy) methyl) nicotinonitrile.

[M + H] < ⁺ >: 263

Step 3) Preparation of 5 - ((2-formyl-5 - ((2-methyl- [1,1'-biphenyl] -1H-3- yl) ethynyl) phenoxy) methyl) nicotinonitrile

5 - ((2-formyl-phenoxy) methyl-5-ethynyl) nicotinonitrile nitrile 1.38 g, 3- bromo-2-methyl-biphenyl 1.10 g, CuI 0.07 g, Pd (PPh 3) 4 0.41 g, Et ₃ N and 14 mL of THF was stirred at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 - ((2-formyl-5 - ((2-methyl- [1,1'-biphenyl] -1H- 3- yl) ethynyl) phenoxy) 1.37 g of nicotinonitrile was obtained.

[M + H] < ⁺ >: 429

Step 4) Synthesis of (2- ((5-cyanopyridin-3-yl) methoxy) -4 - ((2- Manufacturing

The title compound was prepared following the procedure described in Example 1 step (b) using 5 - ((2-formyl-5 - ((2-methyl- [1,1'- biphenyl] -1H-3- yl) ethynyl) phenoxy) 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl ) Benzyl) glycine.

[M + H] < ⁺ >: 488

Example 25 Preparation of 5 - ((5 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl- (2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinonitrile

Step 1) Preparation of 5 - ((5-bromo-2-formylphenoxy) methyl) nicotinonitrile

A mixture of 0.50 g of 4-bromo-2-hydroxybenzaldehyde, 1.00 g of triphenylphosphine (PPh ₃ ), 0.37 g of 5- (hydroxymethyl) nicotinonitrile and 5 mL of THF was stirred at 0 ° C for 30 minutes After that, a mixed solution of 0.60 g of diisopropyl azodicarboxylate and 2 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.40 g of 5 - ((5-bromo-2-formylphenoxy) methyl) nicotinonitrile

[M + H] < ⁺ >: 317

Step 2) Preparation of ((3-bromo-2-methylphenyl) ethynyl) trimethylsilane

A mixture of 10.00 g of 1-bromo-3-iodo-2-methylbenzene, 4.96 g of ethynyltrimethylsilane, 0.64 g of CuI, 2.36 g of PdCl ₂ (PPh ₃ ) ₂ , 5.11 g of Et ₃ N and 100 mL of THF Was bubbled with nitrogen gas at room temperature, and then stirred at 70 占 폚 for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.80 g of ((3-bromo-2-methylphenyl) ethynyl) trimethylsilane.

[M + H] < ⁺ >: 268

Step 3) Preparation of ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) trimethylsilane

9.59 g of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) boronic acid, 9.50 g of Pd ((3-bromo-2-methylphenyl) ethynyl) trimethylsilane, _{PPh 3) 4 2.06 g, CsCO} 3 17.41 g, was in water 10 mL, 70 ℃ di after bubbling with nitrogen gas, a mixture of 60 mL dioxane was stirred at room temperature for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.00 g of (3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) trimethylsilane ≪ / RTI >

[M + H] < ⁺ >: 323

Step 4) Preparation of 6- (3-ethynyl-2-methylphenyl) -2,3-dihydrobenzo [b] [1,4]

(6.00 g of (3- (2,3- dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) trimethylsilane, tetrabutylammonium fluoride ), And 6 mL of THF was stirred at room temperature for 4 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.20 g of 6- (3-ethynyl-2-methylphenyl) -2,3-dihydrobenzo [b] [1,4]

[M + H] < ⁺ >: 251

Step 5) Synthesis of 5 - ((5 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) -2- ) Methyl) nicotinonitrile < / RTI >

1.3 g of 6- (3-ethynyl-2-methylphenyl) -2,3-dihydrobenzo [b] [1,4 ] Dioxin, 0.10 g of CuI, 0.36 g of PdCl ₂ (PPh ₃ ) ₂ , 0.79 g of Et ₃ N and 26 mL of THF was bubbled with a nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 - ((5 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ) -2-formylphenoxy) methyl) nicotinonitrile (1.40 g).

[M + H] < ⁺ >: 487

Step 6) Preparation of 5 - ((5 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl- 2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinonitrile

Ethynyl) -2-formylphenoxy) methyl) -2-methylphenyl) ethoxy] -5- { 0.30 g of nicotinonitrile, 0.21 g of ethanolamine, 0.26 g of NaBH (OAc) _{3 and} 3 mL of CH ₂ Cl ₂ was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 - ((5 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ) -2 - (((2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinonitrile.

[M + H] < ⁺ >: 532

Example 26 Synthesis of (2 - ((5-cyanopyridin-3-yl) methoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- Yl) -2-methylphenyl) ethynyl) benzyl) -L-serine

Ethynyl) -2-formylphenoxy) methyl) -2-methylphenyl) ethoxy] -5- { 1.30 g of nicotinonitrile, 0.56 g of L-serine, 1.13 g of NaBH (OAc) ₃ and 13 mL of DMF was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2 - ((5-cyanopyridin-3-yl) methoxy) -4 - ((3- (2,3-dihydrobenzo [ Dioxin-6-yl) -2-methylphenyl) ethynyl) benzyl) -L-serine 0.39 g was obtained.

[M + H] < ⁺ >: 576

Example 27 Synthesis of ((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Manufacturing

Step 1) Preparation of methyl 6-chloro-4-hydroxypyridazine-3-carboxylate

A mixture of 20.05 g of methyl 6-chloro-4-methoxypyridazine-3-carboxylate and 200 mL of CH ₂ Cl _{2 was} stirred at -78 ° C for 30 minutes. A mixture of 100.10 g of boron tribromide (BBr ₃ ) and 100 mL of CH ₂ Cl ₂ was added dropwise over 1 hour, and then the mixture was slowly warmed to room temperature. After stirring overnight at room temperature, water was slowly added dropwise. The mixture was extracted with ethyl ether. The organic layer was washed with 2N aqueous NaOH solution and neutralized with dilute hydrochloric acid. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.17 g of methyl 6-chloro-4-hydroxypyridazine-3-carboxylate.

[M + H] < ⁺ >: 189

Step 2) Preparation of methyl 6-chloro-4- (cyclohexylmethoxy) pyridazine-3-carboxylate

A mixture of 1.00 g of methyl 6-chloro-4-hydroxypyridazine-3-carboxylate, 2.09 g of triphenylphosphine (PPh ₃ ), 0.67 g of cyclohexylmethanol and 10 mL of THF was stirred at 0 ° C for 30 minutes , 1.18 g of diisopropyl azodicarboxylate and 4 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.06 g of methyl 6-chloro-4- (cyclohexylmethoxy) pyridazine-3-carboxylate

[M + H] < ⁺ >: 285

Step 3) Preparation of 1-bromo-3-ethynyl-2-methylbenzene

A mixture of 40.00 g of 1-bromo-3-iodo-2-methylbenzene, 19.86 g of ethynyltrimethylsilane, 2.57 g of CuI, 9.47 g of PdCl ₂ (PPh ₃ ) ₂ , 20.47 g of Et ₃ N and 400 mL of THF Was bubbled with nitrogen gas at room temperature, and then stirred at 70 占 폚 for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (400 mL), and 160 g of K ₂ CO ₃ was added dropwise thereto. The mixture was stirred at room temperature for 6 hours, filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 23.72 g of 1-bromo-3-ethynyl-2-methylbenzene.

[M + H] < ⁺ >: 195

Step 4) Preparation of 3-ethynyl-2-methyl-1,1'-biphenyl

2-methyl-benzene ethynyl, 1-bromo--3- 10.00 g, phenylboronic acid _{(PhB (OH) 2) 9.31} g, Pd (PPh 3) 4 2.96 g, CsCO 3 25.00 g, water 10 mL, dioxane 60 mL was bubbled with nitrogen gas at room temperature and stirred at 70 캜 for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.08 g of 3-ethynyl-2-methyl-1,1'-biphenyl.

[M + H] < ⁺ >: 193

Step 5) Preparation of methyl 4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-

Methyl 6-chloro-4- (cyclohexyl silme ethoxy) pyridazin-3-carboxylate 0.40 g, 3-ethynyl-2-methyl-1,1'-biphenyl 0.41 g, CuI 0.03 g, PdCl 2 (PPh ₃ ) ₂ , 0.21 g of Et ₃ N and 8 mL of THF was bubbled with nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- 0.56 g of carboxylate was obtained.

[M + H] < ⁺ >: 441

Step 6) Preparation of 4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carboaldehyde

Methyl 4- (cyclohexyl silme ethoxy) -6- chopped - ((2-methyl [1,1'-biphenyl] ethynyl-3-yl)) pyrimidin-3-carboxylate 0.50 g, 5 CH ₂ Cl ₂ mL was treated with Dibal-H (( i- Bu) ₂ AlH, 1 M in toluene) at 0 ° C and stirred for 1 hour. After completion of the reaction, the reaction mixture was treated with sodium potassium tartrate solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3- yl) ethynyl) pyridazine- 0.46 g of aldehyde was obtained.

[M + H] < ⁺ >: 411

Step 7) Synthesis of tert-butyl ((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3- ylethynyl) pyridazin- ) Preparation of glycinate

0.20 g of 4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carboaldehyde, 0.13 g of NaBH (OAc) _3, 0.21 g of NaBH (OAc) _{3 and} 2 mL of CH ₂ Cl ₂ was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl ((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3- Yl) methyl) glycinate was obtained.

[M + H] < ⁺ >: 526

Step 8) Synthesis of ((4-cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Produce

((4- (cyclohexylmethoxy) -6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- A mixture of 0.10 g of nate, 0.22 g of trifluoroacetic acid and 1 mL of CH ₂ Cl ₂ was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and aqueous NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography afforded ((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Methyl) glycine.

[M + H] < ⁺ >: 470

Example 28) Synthesis of 2 - (((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3- yl) ethynyl) pyridazin- Methyl) amino) ethan-1-ol < / RTI >

0.10 g of 4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazine-3-carboaldehyde, 0.03 g of ethanolamine, (OAc) ₃ (0.10 g) and CH ₂ Cl _{2 (} 1 mL) was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2 - (((4- (cyclohexylmethoxy) -6- (2-methyl- [1,1'-biphenyl] -3- 3-yl) methyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 456

Example 29: Synthesis of ((4- (cyclohexylmethoxy) -6 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin-6-yl) Yl) pyridazin-3-yl) methyl) glycine

Step 1) Preparation of methyl 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Preparation of pyridazine-3-carboxylate

A solution of 0.50 g of methyl 6-chloro-4- (cyclohexylmethoxy) pyridazine-3-carboxylate and 0.50 g of 6- (3-ethynyl-2-methylphenyl) -2,3- dihydrobenzo [ ] Dioxin, 0.03 g of CuI, 0.12 g of PdCl ₂ (PPh ₃ ) ₂ , 0.26 g of Et ₃ N and 10 mL of THF was bubbled with a nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- -Methylphenyl) ethynyl) pyridazine-3-carboxylate (0.63 g).

[M + H] < ⁺ >: 499

Step 2) Synthesis of 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) Preparation of choline-3-carboaldehyde

(Methyl) 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) A mixture of 0.50 g of 3-carboxylate and 5 mL of CH ₂ Cl ₂ was treated with 1.10 mL of Dibal-H (( i- Bu) ₂ AlH, 1 M in toluene) at 0 ° C and stirred for 1 hour. After completion of the reaction, the reaction mixture was treated with sodium potassium tartrate solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- -Methylphenyl) ethynyl) pyridazine-3-carboaldehyde (0.46 g).

[M + H] < ⁺ >: 469

Step 3) Synthesis of tert-butyl ((4- (cyclohexylmethoxy) -6- (3- (2,3-dihydrobenzo [b] [1,4] dioxin- ) Ethynyl) pyridazin-3-yl) methyl) glycinate

Dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) pyridazine-3 -Carbaldehyde (0.20 g), tert-butyl glycinate (0.11 g), NaBH (OAc) ₃ (0.18 g) and CH ₂ Cl _{2 (} 2 mL) was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl ((4- (cyclohexylmethoxy) -6 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- Yl) -2-methylphenyl) ethynyl) pyridazin-3-yl) methyl) glycinate.

[M + H] < ⁺ >: 584

Step 4) Synthesis of (4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ) Pyridazin-3-yl) methyl) glycine

Butyl ((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ) Pyridazin-3-yl) methyl) glycinate, 0.03 g of NaOH and 1 mL of MeOH was stirred at room temperature for 4 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of ethyl acetate and NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography ((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- -2-methylphenyl) ethynyl) pyridazin-3-yl) methyl) glycine.

[M + H] < ⁺ >: 528

Example 30 Preparation of 2 - (((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Methylphenyl) ethynyl) pyridazin-3-yl) methyl) amino) ethan-1-ol

Example 29 To a solution of 4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ((4- (cyclohexylmethoxy) -6- (3- (2, 3-dihydrobenzo [iota] yl) pyridazin-3-carboaldehyde was prepared in the same manner as in Example 28, b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) pyridazin-3-yl) methyl) amino) ethan- 1 -ol.

[M + H] < ⁺ >: 514

Example 31: Preparation of 2 - (((3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin- ) Amino) ethan-1-ol < / RTI >

Step 1) Preparation of 5-bromo-3- (cyclohexylmethoxy) picolinonitrile

A mixture of 2.00 g of 5-bromo-3-hydroxy-picolinonitrile, 3.95 g of triphenylphosphine (PPh ₃ ), 1.26 g of cyclohexylmethanol and 20 mL of THF was stirred at 0 ° C for 30 minutes, 2.23 g of propyl azodicarboxylate and 8 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.93 g of 5-bromo-3- (cyclohexylmethoxy) picolinonitrile

[M + H] < ⁺ >: 296

Step 2) Preparation of 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) picolinonitrile

Using 5-bromo-3- (cyclohexylmethoxy) picolinonitrile and 3-ethynyl-2-methyl-1,1'-biphenyl prepared in step 4 of Example 27, In the same manner, 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) picolinonitrile was obtained.

[M + H] < ⁺ >: 407

Step 3) Preparation of 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) picoline aldehyde

A mixture of 1.00 g of 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) picolinonitrile and 10 mL of CH ₂ Cl ₂ was treated with 0 The reaction mixture was treated with 2.21 mL of Dibal-H (( i- Bu) ₂ AlH, 1 M in toluene) and stirred for 1 hour. After completion of the reaction, the reaction mixture was treated with sodium potassium tartrate solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.53 g of 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'- biphenyl] -3-yl) ethynyl) picoline aldehyde .

[M + H] < ⁺ >: 410

Step 4) Synthesis of 2 - (((3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'- biphenyl] -3- ylethynyl) pyridin- Amino) ethan-1-ol < / RTI >

The title compound was obtained as a pale yellow solid by the same method as in Example 28, using 3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3- ((3- (cyclohexylmethoxy) -5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin- Respectively.

[M + H] < ⁺ >: 455

Example 32 Preparation of (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

Step 1) Preparation of 4-bromo-2- (cyclohexylmethoxy) benzaldehyde

A mixture of 5.00 g of 4-bromo-2-hydroxybenzaldehyde, 9.78 g of triphenylphosphine (PPh ₃ ), 3.12 g of cyclohexylmethanol and 50 mL of THF was stirred at 0 ° C for 30 minutes and then diisopropyl azo 5.53 g of dicarboxylate, and 20 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.43 g of 4-bromo-2- (cyclohexylmethoxy) benzaldehyde

[M + H] < ⁺ >: 298

Step 2) Preparation of 2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzaldehyde

0.97 g of 3-ethynyl-2-methyl-1,1'-biphenyl, 0.06 g of CuI and 0.24 g of PdCl ₂ (PPh ₃ ) ₂ were added to a solution of 1.00 g of 4-bromo-2- (cyclohexylmethoxy) benzaldehyde, 0.51 g of Et ₃ N and 20 mL of THF was bubbled with a nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.48 g of 2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzaldehyde .

[M + H] < ⁺ >: 409

Step 3) Preparation of tert-butyl (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycinate

0.20 g of 2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzaldehyde, 0.13 g of tert- butylglycinate, OAc) _{3 (} 0.21 g) and CH ₂ Cl _{2 (} 2 mL) was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] 0.18 g of glycinate was obtained.

[M + H] < ⁺ >: 524

Step 4) Preparation of (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

0.10 g of tert-butyl (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycinate, 0.22 g and 1 mL of CH ₂ Cl ₂ was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and aqueous NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.07 g of (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine.

[M + H] < ⁺ >: 468

Example 33) 2 - ((2- (Cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) amino) Manufacturing

(2- (cyclohexyl silme ethoxy) -4 - ((2-methyl- [1,1'-biphenyl] _3-yl) ethynyl) benzaldehyde 0.10 g, ethanolamine 0.03 g, NaBH (OAc) 0.10 g, CH ₂ and the mixture was stirred at room temperature for 6 hours a mixture of Cl ₂ 1 mL. after completion of the reaction, was dried, and then the organic layer gave wipe with a NH ₄ Cl aqueous solution over anhydrous Na ₂ SO ₄ and the solvent was distilled out under a filtration pressure The residue was purified by silica gel column chromatography to give 2 - ((2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3- ) Amino) ethan-1-ol (0.08 g).

[M + H] < ⁺ >: 454

Example 34 Synthesis of 2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ) Benzyl) glycine

Step 1) Synthesis of 2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) Preparation of aldehyde

Dihydrobenzo [b] [1,4] dioxin 1.26 g (1.00 g) was added to a solution of 1.00 g of 4-bromo- (2- (cyclohexylmethoxy) benzaldehyde and 6- g, 0.06 g of CuI, 0.24 g of PdCl ₂ (PPh ₃ ) ₂ , 0.51 g of Et ₃ N and 15 mL of THF was bubbled with nitrogen gas at room temperature and stirred for 24 hours at 70 ° C. After completion of the reaction, ethyl The organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (cyclohexylmethoxy) -4 - (( To obtain 1.34 g of 3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) benzaldehyde.

[M + H] < ⁺ >: 467

Step 2) (2- (Cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Benzyl) glycine

Using 2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylphenyl) ethynyl) benzaldehyde Example 29 By the same procedure as in steps 3 and 4, the title compound was obtained from ((2- (cyclohexylmethoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- ) -2-methylphenyl) ethynyl) benzyl) glycine.

[M + H] < ⁺ >: 526

Example 35) Synthesis of 2 - ((2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- ) Ethynyl) benzyl) amino) ethan-1-ol < / RTI &

Example 34 To a solution of 2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Ethynyl) benzaldehyde, 2 - ((2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] di Oxyn-6-yl) -2-methylphenyl) ethynyl) benzyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 512

Ethoxy) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl) Production of glycine

Step 1) Preparation of 4-bromo-2- ((1-methylpiperidin-4-yl) methoxy) benzaldehyde

4-Bromo-2-hydroxy benzaldehyde 5.00 g, triphenylphosphine (PPh ₃₎ 9.78g, (1- methyl Pieper naphthyridin-4-yl) methanol 3.53 g, 30 a mixture of 50 mL THF at 0 ℃ After stirring for a minute, a mixed solution of 5.53 g of diisopropyl azodicarboxylate and 20 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.96 g of 4-bromo-2 - ((1-methylpiperidin-4-yl) methoxy) benzaldehyde

[M + H] < ⁺ >: 313

Step 2) Preparation of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2 - ((1-methylpiperidin-4- yl) methoxy) benzaldehyde

1.00 g of 4-bromo-2 - ((1-methylpiperidin-4-yl) methoxy) benzaldehyde, 0.92 g of 3-ethynyl- 0.22 g of PdCl ₂ (PPh ₃ ) ₂ , 0.49 g of Et ₃ N and 20 mL of THF was bubbled with nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- Methoxy) benzaldehyde (1.12 g).

[M + H] < ⁺ >: 424

Ethynyl) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl) glycine Manufacturing

The title compound was obtained as a yellow amorphous solid in the same manner as in Example 32 (2) using 4 - ((2-methyl- [1,1'-biphenyl] -3- Ethynyl) -2 - ((1-methylpiperidin-4-yl) methyl) -1,2,3,4-tetrahydrobenzo [ Benzyl) glycine. ≪ / RTI >

[M + H] < ⁺ >: 483

Example 37: 2 - ((4 - ((2-Methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- ) Benzyl) amino) ethan-1-ol < / RTI >

2- ((1-methylpiperidin-4-yl) methoxy) - (2-methyl- [1,1'- Ethynyl) -2 - ((1-methylpiperidine (1-methylpiperidine-2-carboxylic acid ethyl ester) Yl) methoxy) benzyl) amino) ethan-l-ol.

[M + H] < ⁺ >: 469

Example 38) Synthesis of (4- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2- (piperidin- 1- yl) ethoxy) benzyl) Manufacturing

Step 1) Preparation of 4-bromo-2- (2- (piperidin-1-yl) ethoxy) benzaldehyde

4-Bromo-2-hydroxy benzaldehyde 5.00 g, triphenylphosphine (PPh ₃₎ 9.78g, 2- (Pieper naphthyridin-1-yl) ethane-1-ol 3.53 g, a mixture of 50 mL THF 0 C for 30 minutes, and then a mixed solution of 5.53 g of diisopropyl azodicarboxylate and 20 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.89 g of 4-bromo-2- (2- (piperidin-1-yl) ethoxy) benzaldehyde

[M + H] < ⁺ >: 313

Step 2) Preparation of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2- (piperidin- 1- yl) ethoxy) benzaldehyde

1.00 g of 4-bromo-2- (piperidin-1-yl) ethoxy) benzaldehyde, 0.92 g of 3-ethynyl-2-methyl-1,1'-biphenyl, 0.06 g of CuI, ₂ (PPh ₃ ) ₂ , 0.49 g of Et ₃ N and 15 mL of THF was bubbled with nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2- (piperidin- Ethoxy) benzaldehyde (1.16 g).

[M + H] < ⁺ >: 424

Step 3) To a solution of (4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- Produce

The title compound was prepared using the procedures described in step 2 of Example 32, step 4, using 4 - ((2-methyl- [1,1'-biphenyl] -3- ylethynyl) -2- (2- (piperidin- 1- yl) ethoxy) benzaldehyde. Ethynyl) -2- (2- (piperidin-1-yl) ethoxy) -2,3- Benzyl) glycine.

[M + H] < ⁺ >: 483

Ethynyl) -2- (2- (piperidin-1-yl) ethoxy) - < / RTI & Benzyl) amino) ethan-1-ol

Ethynyl) -2- (2- (piperidin-1-yl) ethoxy) benzene obtained in step 2 and 4- ( Ethynyl) -2- (2- (piperidin-1-ylmethyl) -1H-imidazol-2-yl) Yl) ethoxy) benzyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 469

Ethoxy) -2- (2- (4-methylpiperazin-1-yl) ethoxy) Benzyl) glycine

Step 1) Preparation of 4-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) benzaldehyde

4-Bromo-2-hydroxy benzaldehyde 5.00 g, triphenylphosphine _{(PPh 3) 9.78g, 2- (} 4- methylpiperazin-1-yl) ethane-1-ol 3.94 g, in 50 mL THF After the mixed solution was stirred at 0 占 폚 for 30 minutes, a mixed solution of 5.53 g of diisopropyl azodicarboxylate and 20 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.47 g of 4-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) benzaldehyde

[M + H] < ⁺ >: 328

Ethynyl) -2- (2- (4-methylpiperazin-1-yl) ethoxy) benzaldehyde Manufacturing

1.05 g of 4-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) benzaldehyde, 0.92 g of 3-ethynyl- g, 0.22 g of PdCl ₂ (PPh ₃ ) ₂ , 0.49 g of Et ₃ N and 20 mL of THF was bubbled with a nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- Yl) ethoxy) benzaldehyde (1.26 g).

[M + H] < ⁺ >: 439

Ethynyl) -2- (2- (4-methylpiperazin-1-yl) ethoxy) benzyl ) Preparation of glycine

Ethynyl) -2- (2- (4-methylpiperazin-1-yl) ethoxy) benzaldehyde as a starting material was carried out using 4- ((2-methyl- [1,1'-biphenyl] -3- Ethynyl) -2- (2- (4-methylpiperazin-1-ylmethyl) -1 H- Yl) ethoxy) benzyl) glycine.

[M + H] < ⁺ >: 498

Example 41: Synthesis of 2 - ((4 - ((2-methyl- [1,1'-biphenyl] -3- Ethoxy) benzyl) amino) ethan-1-ol

Example 40 To a solution of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- Ethynyl) -2- (2- (4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzaldehyde was obtained in the same manner as in Example 33, -Methylpiperazin-1-yl) ethoxy) benzyl) amino) ethan-1-ol.

[M + H] < ⁺ >: 484

Example 42 Preparation of (4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl)

Step 1) Preparation of 4-bromo-2- (2-morpholinoethoxy) benzaldehyde

A mixture of 5.00 g of 4-bromo-2-hydroxybenzaldehyde, 9.78 g of triphenylphosphine (PPh ₃ ), 3.58 g of 2-morpholinoethan-1-ol and 50 mL of THF was stirred at 0 ° C for 30 minutes Then, a mixture of 5.53 g of diisopropyl azodicarboxylate and 20 mL of THF was slowly added dropwise. The mixture was stirred at room temperature. After completion of the reaction, the mixture was solidified by adding cold hexane and then filtered, and the filtrate was subjected to removal of the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.08 g of 4-bromo-2- (2-morpholinoethoxy) benzaldehyde

[M + H] < ⁺ >: 315

Step 2) Preparation of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzaldehyde

4-Bromo-2- (2-Dimorpholino Reno ethoxy) benzaldehyde 1.00 g, 2-methyl-1,1'-phenyl ethynyl-3- 0.92 g, CuI 0.06 g, PdCl 2 (PPh 3) 2 0.22 g of Et ₃ N, 0.49 g of Et ₃ N and 20 mL of THF was bubbled with nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.44 g of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzaldehyde ≪ / RTI >

[M + H] < ⁺ >: 426

Step 3) Preparation of (4- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl) glycine

Ethynyl) -2- (2-morpholinoethoxy) benzaldehyde was used in place of 4 - ((2-methyl- [1,1'-biphenyl] -3- Ethynyl) -2- (2-morpholinoethoxy) benzyl) glycine was obtained in the same manner as in (1).

[M + H] < ⁺ >: 485

Ethynyl) -2- (2-morpholinoethoxy) benzyl) amino) ethane-1-carboxylic acid Preparation of 1-ol

Example 42 Using 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzaldehyde obtained in Step 2, Ethynyl) -2- (2-morpholinoethoxy) benzyl) amino) ethane-2-carboxylic acid 1-ol.

[M + H] < ⁺ >: 471

Example 44 Synthesis of 1- (4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl) piperidin- Preparation of carboxylic acid

Example 42 To a solution of 4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzaldehyde obtained in step 2 and methyl piperidine- 2- (2-methyl- [l, r-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl) piperidine-2-carboxylic acid.

[M + H] < ⁺ >: 539

Example 45) Synthesis of 3 - ((3- (cyclohexylmethoxy) -4 - ((2-hydroxyethyl) amino) methyl) phenyl) ethynyl- [1,1'- Preparation of Carbonitrile

Step 1) Preparation of 1-bromo-3-ethynyl-2-benzonitrile

A mixture of 10.00 g of 2-bromo-6-iodobenzonitrile, 5.00 g of ethynyltrimethylsilane, 0.64 g of CuI, 2.36 g of PdCl ₂ (PPh ₃ ) ₂ , 5.0 g of Et ₃ N and 100 mL of THF was stirred at room temperature The mixture was bubbled with nitrogen gas and stirred at 70 DEG C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 100 mL of methanol, 40 g of K ₂ CO ₃ was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.11 g of 1-bromo-3-ethynyl-2-benzonitrile.

[M + H] < ⁺ >: 207

Step 2) Preparation of 3-ethynyl- [1,1'-biphenyl] -2-carbonitrile

Benzonitrile 2-ethynyl-1-bromo--3- 5.00 g, phenylboronic acid _{(PhB (OH) 2) 4.60} g, Pd (PPh 3) 4 1.50 g, CsCO 3 13.00 g, water 5 mL, dioxane 30 mL of the mixture was bubbled with nitrogen gas at room temperature, followed by stirring at 70 占 폚 for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.57 g of 3-ethynyl- [1,1'-biphenyl] -2-carbonitrile.

[M + H] < ⁺ >: 204

Step 3) Preparation of 3 - ((3- (cyclohexylmethoxy) -4-formylphenyl) ethynyl- [1,1'-biphenyl] -2-carbonitrile

0.97 g of 3-ethynyl- [1,1'-biphenyl] -2-carbonitrile, 0.06 g of CuI, 0.06 g of PdCl ₂ (PPh ₃ ) ₂ , 0.51 g of Et ₃ N and 20 mL of THF was bubbled with nitrogen gas at room temperature, followed by stirring at 70 ° C for 24 hours. After completion of the reaction, ethyl acetate and water were added to extract. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.17 g of 3 - ((3- (cyclohexylmethoxy) -4-formylphenyl) ethynyl) - [1,1'- biphenyl] -2-carbonitrile .

[M + H] < ⁺ >: 420

Step 4) Synthesis of 3 - ((3- (cyclohexylmethoxy) -4 - ((2-hydroxyethyl) amino) methyl) phenyl) ethynyl- [1,1'-biphenyl] Manufacture of nitrile

3 - ((3- (cyclohexyl silme ethoxy) ethynyl-4-formyl-phenyl)) - [1,1'-biphenyl] -2-carbonitrile 0.10 g, ethanolamine _{0.03 g, NaBH (OAc) 3} 0.10 g and 1 mL of CH ₂ Cl ₂ was stirred at room temperature for 6 hours. After completion of the reaction, the organic layer was washed with an aqueous solution of NH ₄ Cl. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3 - ((3- (cyclohexylmethoxy) -4 - (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) - [ 0.0 > biphenyl] -2-carbonitrile < / RTI >

[M + H] < ⁺ >: 465

Experimental Evaluation of the inhibition of the interaction of the protein with the programmed death-ligand 1 (PD-1)

Streptavidin-XL (CisBio), PD-1-Eu (1 nM) and the test compound were mixed. PD-L1-biotin (50 nM) was added dropwise to initiate the binding reaction. TR-FRET 665/620 was measured after 1 hour incubation at room temperature.

Compounds were found to be useful for the prevention or treatment of cancer and immune diseases by inhibiting the binding action of PD-1 protein and PD-L1 protein at the treated concentration. Table 1 shows the degree of inhibition of PD-1 protein and PD-L1 protein interaction of the selected compounds.

Example	Inhibition of PD-1 and PD-L1 binding activity
22	> 50% at 1 uM
23	> 50% at 1 uM
25	> 50% at 1 uM
26	> 50% at 1 uM

Claims (8)

1. A pharmaceutical composition for preventing or treating cancer or an immunological disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

   [Chemical Formula 1]

   

   In this formula,

   X ₁ = X ₂ can be N = CR ₁₁ , R ₁₁ -C = N, N = N, C = C;

   R ₁ is _{(CH) n -CO 2 H,} OR 9, CO- (NH-R 9), CO-R 9, NH-R 9, N (R 9) 2, N (R 9) (R 10) ,

   

   , Where n may be from 0 to 4;

   R ₂ is selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, CN, CO- (C _1-4 alkyl), OH, O- (C _1-4 alkyl), O- (CH ₂ ) _m- (CH _{2) m} - alkyl cycle, O- (CH _{2) m} - heterocyclyl, NH _2, NH- (C _1-4 alkyl), N (C _1-4 alkyl _{2, NH- (CH 2) m} - Heteroaryl, SO ₂ - (C _1-4 alkyl), wherein m may be from 0 to 4;

   (C _1-4 alkyl), NH ₂ , NH- (C _1-4 alkyl), and R ₃ , R ₆ , R ₇ , R ₈ and R ₁₁ are independently selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, ), N (C _1-4 alkyl) ₂ , SO ₂ - (C _1-4 alkyl), CO-NH ₂ , CO- (NH-R ₉ );

   R ₄ is hydrogen, halogen, C _1-4 alkyl, CN, CO- (C _1-4 alkyl), OH, O- (C _1-4 alkyl), NH _2, NH- (C _1-4 alkyl), N (C _1-4 alkyl) ₂ ;

   R ₅ is aryl, heteroaryl, alkyl-cycle, may be a heterocycle, which is hydrogen, halogen, C _1-4 alkyl, CN, OH, O- (C _{1-4 alkyl), O- (CH 2) q} - O, NH ₂ , NH- (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , SO ₂ - (C _1-4 alkyl), wherein q is 1 to 4 Lt; / RTI >

   R ₉ and R ₁₀ may be C _1-4 alkyl which may be substituted by halogen, C _1-3 alkyl, CN, OH, CO ₂ H, CONH ₂ , NH ₂ , NH- (C _1-3 alkyl) C _1-3 alkyl) ₂ ,

   

   , N-CO-C _1-4 alkyl, wherein x can be from 0 to 4;

   Halogen can be F, Cl, Br.
2. The method according to claim 1,

   R ₁ is OR ₉ , NH-R ₉ ,

   

   Or a pharmaceutically acceptable salt thereof as an active ingredient.
3. The method according to claim 1,

   R ₂ is hydrogen, halogen, methyl, ethyl, CN, OH, OMe, OEt, O- (CH ₂₎ - heteroaryl, O- (CH _{2) 2} - heteroaryl, O- (CH ₂₎ - alkyl-cycle, O- (CH _{2) 2} - cycle alkyl, O- (CH ₂₎ - heterocycle, O- (CH _{2) 2} - _{heterocyclic, NH 2, NHMe, NMe2,} N- (CH 2) - heteroaryl, N - (CH ₂ ) ₂ -heteroaryl, or a pharmaceutically acceptable salt thereof, as an active ingredient.
4. The method according to claim 1,

   Wherein R ₃ , R ₄ , R ₆ , R ₇ , R ₈ and R ₁₁ are hydrogen, halogen, methyl, ethyl, cyclopropyl, CN, OH, OMe, OEt, NH ₂ , NHMe, NMe ₂ Or a pharmaceutically acceptable salt thereof as an active ingredient.
5. The method according to claim 1,

   R ₅ is phenyl, thiophene, pyridine, pyrimidine, pyridazine, oxazole,

   

   ,

   

   ,

   

   It characterized in that, which is hydrogen, halogen, methyl, ethyl, and CN, OH, OMe, OEt, O- (CH 2) -O, O- (CH 2) 2 -O, NH 2, NHMe, NMe 2, SO ₂ Me, or a pharmaceutically acceptable salt thereof as an active ingredient.
6. The method according to claim 1,

   R _9, R ₁₀ is characterized in that the C _1-4 alkyl, which halogen, methyl, ethyl, CN, OH, CO ₂ H, CONH _2, NH _2, NHMe, NHEt, NMe _2, N-CO-Me Or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The method according to claim 1,

   1) ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

   2) 1 - ((6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine- 2-

   3) Ethyl) pyridazin-3-yl) methyl) amino) ethan-1-ol

   4) ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3- yl) ethynyl) pyridazin-

   5) Preparation of 1 - ((6 - ((5-fluoro-2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin- Carboxylic acid

   Ethynyl) pyridazin-3-yl) methyl) amino) ethane-2-carboxylic acid 1-

   7) ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

   8) Synthesis of 1 - ((6 - ((2-cyano- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl) piperidine-

   9) Preparation of 2 - (((6 - ((2-cyano- [

   Ethynyl) pyridazin-3-yl) methyl) glycine (2-methyl-

   Ethyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid (2-methyl-

   Ethynyl) pyridazin-3-yl) methyl) amino) ethane-1, 2- - All

   13) ((5-Chloro-6 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-

   Ethyl) pyridazin-3-yl) methyl) piperidine-2-carboxylic acid (2-methyl-

   Ethynyl) pyridazin-3-yl) methyl) amino) ethane-1, 2'- - All

   16) ((6- ((2-methyl-3- (pyridin-4- yl) phenyl) ethynyl) pyridazin-

   17) ((6 - ((2-methyl-2 ', 3', 4 ', 5'-tetrahydro- [1,1'- biphenyl] -3- yl) ethynyl) pyridazin- ) Methyl) glycine

   Ethynyl) pyridazin-3-yl) methyl) glycine (2-methyl-3-

   19) ((6- ((2-hydroxy- [1,1'-biphenyl] -3-yl) ethynyl) pyridazin-3- yl) methyl)

   20) ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-

   21) ((5 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) pyridin-

   22) (4- ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

   23) 2 - ((4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) amino)

   24) (2- ((5-cyanopyridin-3-yl) methoxy) -4 - ((2-

   Ethynyl) -2 - (((2 (R) -2,5-dihydrobenzo [ -Hydroethyl) amino) methyl) phenoxy) methyl) nicotinonitrile

   26) (2 - ((5-cyanopyridin-3-yl) methoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- -2-methylphenyl) ethynyl) benzyl) -L-serine

   Ethyl) pyridazin-3-yl) methyl) glycine, (2-methyl- [1,1'-biphenyl]

   Yl) ethynyl) pyridazin-3-yl) methyl) - < / RTI & Amino) ethan-1-ol

   29) ((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Pyridazin-3-yl) methyl) glycine

   30) 2 - (((4- (cyclohexylmethoxy) -6 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin- Ethynyl) pyridazin-3-yl) methyl) amino) ethan-1-ol

   Ethynyl) pyridin-2-yl) methyl) amino (2-methylphenyl) ) Ethan-1-ol

   32) (2- (cyclohexylmethoxy) -4 - ((2-methyl- [1,1'-biphenyl] -3-yl) ethynyl) benzyl) glycine

   Ethyl) benzyl) amino) ethan-1-ol (Compound No. 2) was obtained in the same manner as in Example 1,

   34) (2- (cyclohexylmethoxy) -4 - ((3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- methylphenyl) ethynyl) benzyl ) Glycine

   35) To a solution of 2 - ((2- (cyclohexylmethoxy) -4 - ((3- (2,3- dihydrobenzo [b] [1,4] dioxin- Yl) benzyl) amino) ethan-1-ol

   Ethynyl) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl) glycine

   Ethynyl) -2 - ((1-methylpiperidin-4-yl) methoxy) benzyl (2-methyl- ) Amino) ethan-1-ol

   Ethynyl) -2- (2- (piperidin- 1 -yl) ethoxy) benzyl) glycine (2-methyl-

   Ethynyl) -2- (2- (piperidin-1-yl) ethoxy) benzyl) -2,3- Amino) ethane-1-ol

   Ethynyl) -2- (2- (4-methylpiperazin-1-yl) ethoxy) benzyl) Glycine

   Ethoxy) -2- (2- (4-methylpiperazin-1-yl) ethoxy) ) ≪ / RTI > benzyl) amino) ethan-

   Ethynyl) -2- (2-morpholinoethoxy) benzyl) glycine (2-methyl-

   Ethynyl) -2- (2-morpholinoethoxy) benzyl) amino) ethane-l- All

   44) 1- (4 - ((2-Methyl- [1,1'-biphenyl] -3-yl) ethynyl) -2- (2-morpholinoethoxy) benzyl) piperidine- mountain

   45) Preparation of 3 - ((3- (cyclohexylmethoxy) -4 - ((2-hydroxyethyl) amino) methyl) phenyl) ethynyl- [1,1'-biphenyl] -2-carbonitrile

   Or a pharmaceutically acceptable salt thereof, as an active ingredient.
8. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.